Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
Sci Rep. 2017 Apr 3;8:45725. doi: 10.1038/srep45725.
Disruption of the epithelium in the female reproductive tract (FRT) is hypothesized to increase HIV infection risk by interfering with barrier protection and facilitating HIV-target cell recruitment. Here we determined whether Tenofovir (TFV), used vaginally in HIV prevention trials, and Tenofovir alafenamide (TAF), an improved prodrug of TFV, interfere with wound healing in the human FRT. TFV treatment of primary epithelial cells and fibroblasts from the endometrium (EM), endocervix (CX) and ectocervix (ECX) significantly delayed wound closure. Reestablishment of tight junctions was compromised in EM and CX epithelial cells even after wound closure occurred. In contrast, TAF had no inhibitory effect on wound closure or tight junction formation following injury. TAF accumulated inside genital epithelial cells as TFV-DP, the active drug form. At elevated levels of TAF treatment to match TFV intracellular TFV-DP concentrations, both equally impaired barrier function, while wound closure was more sensitive to TFV. Furthermore, TFV but not TAF increased elafin and MIP3a secretion following injury, molecules known to be chemotactic for HIV-target cells. Our results highlight the need of evaluating antiretroviral effects on genital wound healing in future clinical trials. A possible link between delayed wound healing and increased risk of HIV acquisition deserves further investigation.
女性生殖道（FRT）上皮细胞的破坏被认为会增加 HIV 感染的风险，因为它会干扰屏障保护并促进 HIV 靶细胞的募集。在这里，我们确定了在 HIV 预防试验中阴道使用的替诺福韦（TFV）和替诺福韦丙酚酯（TAF），一种 TFV 的改良前药，是否会干扰人 FRT 的伤口愈合。TFV 处理子宫内膜（EM）、宫颈内口（CX）和宫颈外口（ECX）的原代上皮细胞和成纤维细胞，显著延迟了伤口闭合。即使在伤口闭合后，EM 和 CX 上皮细胞中的紧密连接的重建也受到了损害。相比之下，TAF 对损伤后的伤口闭合或紧密连接形成没有抑制作用。TAF 在生殖道上皮细胞内积累为 TFV-DP，即活性药物形式。在升高的 TAF 治疗水平以匹配 TFV 细胞内 TFV-DP 浓度时，两者同样损害了屏障功能，而伤口闭合对 TFV 更敏感。此外，TFV 而非 TAF 增加了损伤后 Elafin 和 MIP3a 的分泌，这些分子已知对 HIV 靶细胞具有趋化作用。我们的结果强调了在未来的临床试验中评估抗逆转录病毒对生殖道伤口愈合的影响的必要性。延迟的伤口愈合与 HIV 感染风险增加之间的可能联系值得进一步研究。
